CN1034132A - 含哌啶基环戊基庚烯酸衍生物的水溶液配方 - Google Patents
含哌啶基环戊基庚烯酸衍生物的水溶液配方 Download PDFInfo
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- RWNJOXUVHRXHSD-UHFFFAOYSA-N hept-6-enoic acid Chemical class OC(=O)CCCCC=C RWNJOXUVHRXHSD-UHFFFAOYSA-N 0.000 title description 2
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- 239000000243 solution Substances 0.000 claims abstract description 87
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- 238000002360 preparation method Methods 0.000 claims abstract description 33
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 12
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims abstract description 10
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- 239000010452 phosphate Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 235000019980 sodium acid phosphate Nutrition 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
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- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical class [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
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- KFXPOIKSDYRVKS-ONEGZZNKSA-N 4-Heptenoic acid Chemical compound CC\C=C\CCC(O)=O KFXPOIKSDYRVKS-ONEGZZNKSA-N 0.000 description 1
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- 229940126062 Compound A Drugs 0.000 description 1
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- 206010038923 Retinopathy Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
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- 239000000443 aerosol Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
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- 229940097362 cyclodextrins Drugs 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical class NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
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- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- CJCPHVRHJKYIJC-UHFFFAOYSA-N methyl 2-hydroxybenzoate;sodium Chemical compound [Na].COC(=O)C1=CC=CC=C1O CJCPHVRHJKYIJC-UHFFFAOYSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
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- Veterinary Medicine (AREA)
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- Nanotechnology (AREA)
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- Crystallography & Structural Chemistry (AREA)
- Pulmonology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本文提供包括[1R-[1α(Z),2β,3β,5α]]-(+)-7-
[5-[[(1,1′-联苯)-4-基]甲氧基]-3-羟基-2-(1-哌
啶基)环戊基]-4-庚烯酸或其盐酸盐与未取代的或取
代的α-,β-,或γ-环糊精的水溶液配方,该配制剂特
别适用于治疗或预防由凝血烷A间接引起的病
症。合适的水溶液配制剂包括注射剂,口服剂如糖浆
和胶囊以及吸入剂。
Description
本发明涉及含有[1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-[[(1,1′-联苯)-4-基]甲氧基]-3-羟基-2-(1-哌啶基)环戊基]-4-庚烯酸(下文称为“化合物A”作为活性成分的水溶液配制剂及其制备方法和它在医学上的用途。
在我们的英国专利号2097397中揭示了作为一组氨基环戊烷衍生物成员之一的化合物A,它具有拮抗内过氧化物(endoperoxide)和凝血噁烷(thromboxane)的作用,并报道了其中这些化合物在治疗气喘和心血管疾病方面是有意义的。最近,我们揭示的化合物A的盐酸盐无论在其制备和在其医学上的应用均优于化合物A及它的其它盐类与溶剂化物。在我们的英国专利号2127406中揭示了该盐酸盐。
不利的是化合物A仅微溶于水并由于化合物A的盐酸盐在接近生理pH时转化成实际上不溶解的化合物A,因而含化合物A盐酸盐与标准赋形剂和/或载体合起来的水溶液配制剂不适于静脉给药。
现在,我们发现当有未取代的或取代的α-,β-,或γ-环糊精(或其水合物)存在时,化合物A或其盐酸盐在水中的溶解度显著提高。我们还发现含有化合物A或其盐酸盐与未取代的或取代的α-,β-,或γ-环糊精(或其水合物)的水溶液配制剂能适用于医用,特别适用于口服、吸入或肠胃外给药,尤其经注射(如静脉注射)给药时,能治疗或预防由于凝血噁烷A2间接引起的病症。
因而,按本发明的一个方面,我们提供一种包括由化合物A或其盐酸盐与未取代的或取代的α-,β-,或γ-环糊精(或其水合物)组成的水溶液配制剂。
本发明的另一方面,我们提供如本文所定义的用于医学,特别是用于治疗或预防由于凝血噁烷A2间接引起的病症的水溶液配制剂。
按本发明的又一方面,我们提供一种治疗由于凝血噁烷A2间接引起的病症的方法,该方法包括对人类或动物患者给以有效量的如本文定义的化合物A水溶液配制剂。
用本发明的水溶液配制剂可治疗的适应症包括在英国专利号2097397和2127406中叙述的使用化合物A或其盐酸盐的其它(如口服)配制剂治疗的那些病症。尤其,本发明的水溶液配制剂可用于治疗或预防血管闭塞疾病,包括心肌梗塞,心脏致死,不固定的心绞痛,瞬间缺血疾病和脑血栓,动脉粥样硬化和血管壁疾病,周围血管疾病,视网膜病,手术后血栓形成和肺栓塞。该水溶液配制剂还可用于预防在进行器官移植(特别是心脏和肾脏)手术前后的并发症,冠状动脉旁路,周围动脉旁路和血栓溶解。该水溶液配制剂还有可能用于有关的消化性溃疡疾病,特别是有可能用于预防已痊愈的消化性溃疡复发。
在本发明的水溶液配制剂中,化合物A最好以它的盐酸盐形式使用。
虽然一般推荐使用单一的环糊精,但是使用多于一种的环糊精可以达到本发明的好处,这将是本领域技术人员可以理解的。
按本发明可使用的取代的环糊精是使用本领域已知的任何合适的取代环糊精。按本发明使用的合适的取代环糊精对本领域的专业人员是容易理解的,它们包括含硫环糊精,含氮环糊精,烷基化(如甲基化)环糊精如一种环糊精(如β-环糊精)的一,二-或三甲基化衍生物以及羟烷基化(如羟丙基化)环糊精,如羟丙基β-环糊精以及这些环糊精的酰化衍生物。现已发现羟烷基(如羟丙基)环糊精例如羟丙基β-环糊精特别适于在本发明中使用。
按本发明可以方便地使用单一种未取代的环糊精。优先的是β-环糊精,以其水合物形式使用是方便的。
为使该水溶液配制剂能显示所需的特性,重要的是调整化合物A或其盐酸盐对所使用的环糊精(或多个环糊精)的摩尔比。我们发现化合物A或其盐酸盐对环糊精(或多种环糊精)的摩尔比在1∶1至1∶4的范围是适宜的。
如果需要,本发明的水溶液配制剂还可以含有一种或多种药物载体或赋形剂,这对于本领域的专业人员也是可以理解的。可以加入该水溶液配制剂中的合适的赋形剂包括能使该配制剂与血浆达到等渗的那些试剂(如氯化钠,葡萄糖或最好是甘露醇),另外还包括缓冲剂(如磷酸盐缓冲剂或酸式磷酸钠和磷酸二钠盐的混合物)。
本发明的水溶液配制剂特别适于肠胃外给药,尤其经注射给药(如静脉注射给药(如静脉注射)。当提供用于肠胃外给药时,使该制剂在大约生理pH是合乎要求的。因而,可以用常规方法如使用合适的碱如氢氧化物(如碱金属氢氧化物,如氢氧化钠溶液)将其pH调节至大约生理pH,将其调节至pH=6.0左右较为适宜。
用于肠胃外给药,尤其用于经注射(如静脉注射)给药时,非常需要提供呈透明溶液的制剂。该透明溶液应不要求进一步处理(如干燥粉末状态)并可以立即给药。应用该透明溶液还可保证容易对产品检查粒子或其它可见的污染物。此外,静脉注射药物水溶液能产生直接的生理作用。我们发现为了在正常贮藏温度时得到接近于生理pH的透明溶液,每一摩尔的化合物A盐酸盐必须至少使用一摩尔的环糊精,但β-环糊精则必须至少使用约1.2摩尔。
由此,本发明的优选实例中,我们提供一种包括化合物A盐酸盐和β-环糊精(或其水合物)在大约生理pH的透明水溶液配方,其中该配方按每一摩尔化合物A盐酸盐至少含有约1.2摩尔的β-环糊精(如1.2至2摩尔),优选的摩尔比约为1∶1.4。
在适用于肠胃外给药,尤其适用于静脉给药(如静脉注射)的上述水溶液配制剂中,化合物A或其盐酸盐的浓度适宜值是0.1-10mg/ml,例如0.1-5mg/ml(以该种游离碱表示)。当该水溶液配方是经静脉注射给药时,最好该浓度为1mg/ml(以该游离碱表示)。如果需要,可以使用较高浓度的溶液,并可以在使用前使用例如等渗盐水溶液或葡萄糖或者甘露醇溶液将该溶液稀释。
适用于注射的溶液以合适剂量体积(如1-100ml)的形式供应较为方便。适用于连续输注的稀释液含化合物A或其盐酸盐的浓度可以是0.01-0.2mg/ml(以该种游离碱表示)。用于连续输注的溶液可以是下述形式,例如以50-100ml包装形式供应,或可以供其后即在使用前用例如等渗盐水溶液或葡萄糖或甘露醇溶液稀释的较浓的形式供应。另一方面,小体积的较浓溶液(如0.1-5mg/ml)可以方便地用于连续输注适宜的给药速率在0.5-9.9ml/h。
本文所述的水溶液配制剂可以方便地制备,只需将化合物A或最好是其盐酸盐与其余组分在水中混合即可。最好先将化合物A或其盐酸盐溶于水中,然后把其余组分加入。供肠胃外给药,尤其是经注射(如静脉注射)给药的溶液,最好将整个溶液过滤,然后灌注入合适的容器内,
最后通过加热彻底灭菌。用另一种方法即该溶液可以用过滤法灭菌,然后以无菌方式灌注入合适的容器内。
当肠胃外配制剂是采用静脉注射或连续输注给药时,应使用可适用于注射的水,这是应注意到的。
供注射的配制剂可以灌装于合适的容器内,如安瓿、小药瓶或预装药液的注射管内的单位剂量形式供应,或可以加有保存剂的多次剂量容器形式供应。
由于上述性能,本发明的水溶液配制剂还可适用于口服给药(如以胶囊、糖浆或溶液形式)或吸入给药(如以气溶胶喷雾方式,方便的是以喷雾剂形式供应)。英国专利号2097397和2127406提供了可适于口服和吸入的配制剂的一般制备方法,该方法对于本发明的用途可以容易地采用而不需要作过多不必要的试验。
水溶液配制剂还可以使用化合物A或其盐酸盐的环糊精固体复合物将它们一起溶于水中来制备,当需要时,可以与前面所规定的一种或多种其它组分一起溶入水中。
因此,在本发明的另一方面,我们提供一个包括化合物A或其盐酸盐和环糊精复合物的水溶液配方。
在本发明的再另一方面,我们提供化合物A或其盐酸盐和环糊精的复合物。当然,在所述的复合物中,化合物A或化合物A盐酸盐与环糊精的比率可显著不同,这取决于所用的环糊精以及为制备该复合物所采用的条件。此外,我们发现化合物A或其盐酸盐与其环糊精的摩尔比在1∶1至1∶3的范围之内是适宜的。
在该固体复合物中使用的环糊精可以是上述定义的未取代的或取代的α-,β-或γ-环糊精,或可以是这些环糊精的混合物(如两种这样的环糊精的混合物。最好使用γ-环糊精或更好是使用β-环糊精。
在本发明的一个具体方面,我们提供化合物A和β-环糊精的复合物,其中化合物A对β-环糊精的摩尔比在1∶1至1∶2范围内,最好为约1∶1。
在本发明的另一具体方面,我们提供化合物A和环糊精复合物,其中化合物A对环糊精的摩尔比是约1∶1.5。
化合物A或其盐酸盐和环糊精的复合物可通过下列方法来制备,即在适当条件下,将化合物A或其盐酸盐与环糊精(或多种环糊精)或其水合物于合适的溶剂中进行混合,由此形成所需的复合物。因而,例如该复合物可以通过下法制备,即将化合物A或其盐酸盐溶于水或与水可混溶的有机溶剂(如醇,例如甲醇)中,然后向该溶液中加入合适的环糊精(或多种环糊精)或其水合物的水溶液或与水相混溶的有机溶剂的溶液。可在0°至80℃的温度范围内进行该反应;然而,该混合物最好保持在室温左右,经减压浓缩该混合物或使该混合物冷却而得到所需要的复合物。根据起始物料和产物的溶解度,有机溶剂与水的混合比例可以明显不同。对于每一摩尔化合物A或其盐酸盐,最好使用1至4摩尔环糊精。
如上操作的结果可以得到具有对高温稳定和良好水溶性的白色固体复合物。这样的物理性质使之特别适用于配制成医学用途的药物制剂。除上述特别适用于肠胃外给药的化合物A或其盐酸盐和环糊精的复合物水溶液配制剂外,该复合物还可以按在英国专利号2097397和2127406中叙述的普通方法配制用于口服、肠胃外或经吸入给药的制剂。
当然,在使用本发明的各配方中的一种配方时,对于化合物A或其盐酸盐的合适日剂量范围是取决于具体的治疗条件,即患者的年令和病情以及给药途径。然而,在英国专利号2097397和2127406中提供的剂量一般是适用的。
下列各实施例意在说明本发明,但不能把其作为对本发明的限制。在下列实施例中的摩尔比率可以通过1H N.M.R.分析测定,所有温度以℃表示。
实施例1
(a)[1R[1α(Z),2β,3β,5α]]-(+)-7-[5-[[1,1′-联苯)-4-基]甲氧基]-3-羟基-2-(1-哌啶基)环戊基]-4-庚烯酸盐:β-环糊精(1∶1)复合物
将β-环糊***合物(0.954g)差不多全溶于水(35ml)。该混悬液经过滤,滤液加到化合物A(0.2g,按GB-B-2097397的实例10)的甲醇(10ml)溶液中。该反应溶液在21℃搅拌26小时得到透明溶液,将其蒸发至体积为12ml,此时该溶液开始产生少量结晶。将该悬浮液冷却至5℃一小时,产生密集的沉淀,滤出沉淀并干燥得到标题化合物(0.273g),m.p.>310℃,在230℃以上色变黑。
(b)从上述实验得到的滤液在放置后开始沉淀出较多的结晶物并由此蒸发至留下白色固体物,将其溶于热水(3ml)中,冷却(5℃)使其结晶得到白色结晶固体(121mg),通过1HN.M.R.(DMSO)分析表明含[1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-[[(1,1′-联苯)-4-基]甲氧基]-3-羟基-2-(1-哌啶基)-环戊基]-4-庚烯酸盐:β-环糊精(1∶1.5)复合物。
实施例2
[1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-[[(1,1′-联苯)-4-基]甲氧基]-3-羟基-2-(1-哌啶基)环戊基]-4-庚烯酸盐:γ-环糊精(1∶1.5)复合物
将γ-环糊精(1.09g)的水(25ml)溶液加至化合物A(0.20g)的甲醇(10ml)溶液中。该反应溶液在21℃搅拌26小时产生稠的白色悬浮液。滤出沉淀并于真空中干燥留下白色固体(0.612g)的标题化合物,m.p.>310℃,在250℃以上色变黑。
肠胃外注射/输注的药物实施例
(ⅰ)化合物A盐酸盐
(相当于50mg碱)
β-环糊***合物 143mg 166mg 238mg
氢氧化钠溶液 加至pH=7 至pH=7 至pH=7
注射用水 加至50ml 至50ml 至50ml
将化合物A的盐酸盐溶于35ml注射用上并加入β-环糊精。该溶液用0.02M氢氧化钠溶液滴加至pH=7然后加入注射用水达到所需体积。
然后将溶液经过滤灭菌,再灌注入小药瓶或安瓿中。
(ⅱ)化合物A盐酸盐
(相当于50mg碱)
β-环糊***合物 166mg
氯化钠 450mg
pH=7.0磷酸盐缓冲液 2.5ml
氢氧化钠溶液 加至pH=7
注射用水 加至50ml
将化合物A盐酸盐溶液约25ml注射用水,再将β-环糊精溶入,产生的溶液用0.02M氢氧化钠滴加至pH=6并加入磷酸盐缓冲液。溶液中加入氯化钠并用氢氧化钠调节至pH=7,加入注射用水使溶液达到所需体积。将该溶液的一个样品灌注入玻璃小药瓶,用橡皮塞和金属外套密封,然后高压蒸汽灭菌处理。
(ⅲ)化合物A盐酸盐
(相当于50mg碱)
羟丙基-β-环糊精 170mg
甘露醇 2.5g
pH=6.0磷酸盐缓冲液 5.0ml
氢氧化钠溶液 加至pH=6
注射用水 加至50ml
将化合物A盐酸盐溶于约25ml注射用水,加入羟丙基-β-环糊精,然后加入甘露醇,该溶液用0.02M氢氧化钠溶液滴加至pH=6,加入磷酸盐缓冲溶液,用注射用水把该溶液调节至所需体积,然后过滤溶液并灌注入玻璃小药瓶,将药瓶用橡皮塞和金属外套密封,再经高压蒸汽灭菌处理。
(ⅳ)化合物A盐酸盐
(相当于50mg碱)
β-环糊***合物 166mg
甘露醇 2.5g
酸式磷酸钠 46mg
无水磷酸二钠盐 5mg
氢氧化钠溶液 加至pH=6
注射用水 加至50ml
将化合物A盐酸盐溶于约25ml注射用水,将β-环糊精和甘露醇溶入其中,该溶液用0.02M氢氧化钠溶液滴加至pH=6。另将酸式磷酸钠和无水磷酸二钠盐溶于注射用水,该溶液加至上面的主体溶液中,加入注射用水达到所需体积,过滤该溶液并灌注入玻璃安瓿内,将安瓿密封再经高压蒸汽灭菌处理。
(v) 环糊精 混合物
α γ β+γ
化合物A盐酸盐
(相当于50mg碱)
环糊精 143mg 190mg 119mg 136mg
甘露醇 2.5g 2.5g 2.5g
pH=6.0磷酸盐缓冲液 5.0ml 5.0ml 5.0ml
氢氧化钠溶液 加至pH=6 pH=6 至pH=6
注射用水 加至50ml 50ml 50ml
将化合物A盐酸盐溶于约25ml注射用水,加入环糊精(或多种环糊精),然后加入甘露醇,用0.02M氢氧化钠溶液将该溶液滴加至pH=6,加入磷酸盐缓冲溶液,加入注射用水将溶液调节至所需体积,然后过滤溶液并灌注入玻璃小药瓶,将药瓶用橡皮塞和金属外套密封。
口服糖浆的药物实施例
化合物A盐酸盐
(相当于2.5mg碱)
β-环糊***合物 9mg
柠檬酸 加至pH=4.5
羟基苯甲酸甲酯钠 5mg
羟基苯甲酸丙酯钠 2mg
液体橙味食用香精 适量
蔗糖 3.25g
纯化水 加至5.0ml
将蔗糖溶于最小量的水中,加入化合物A盐酸盐,然后边搅拌边加入β-环糊精,用柠檬酸将溶液pH调节至4.5,继续搅拌加入羟基苯甲酸酯溶液,最后加入香精。加水将溶液调至接近所需体积并搅拌,如需要,可以用柠檬酸校正pH至4.5,再加水达到所需体积。
用于吸入的溶液的药物实施例
化合物A盐酸盐 每2ml剂量
(相当于2mg碱)
β-环糊***合物 7mg
氯化钠 18mg
氢氧化钠溶液 加至pH=7.2
pH=7.2磷酸盐缓冲液 0.2ml
注射用水 加至2ml
将化合物A盐酸盐溶于注射用水,将β-环糊精溶于其中,以氢氧化钠溶液将产生的溶液调节至pH=6;加入磷酸盐缓冲溶液,加入氯化钠,用氢氧化钠溶液调节至pH=7.2,以注射用水将溶液配制至所需体积,通过过滤灭菌,无菌灌注入适于喷雾吸入的容器内。
Claims (10)
1、一种制备含有[1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-[[(1,1′-联苯)-4-基]甲氧基]-3-羟基-2-(1-哌啶基)环戊基]-4-庚烯酸(化合物A)作为活性成分的水溶液配制剂的方法,该方法包括将化合物A或其盐酸盐与未取代的或取代的α-,β-或γ-环糊精或其水合物在水中进行混合。
2、按权利要求1所要求的方法,其中将化合物A或其盐酸盐溶于水,然后加入其余组分。
3、按权利要求1或2所要求的方法,其中化合物A是以其盐酸盐形式使用。
4、按权利要求1-3中任一项所要求的方法,其中应用的环糊精是β-环糊精。
5、按权利要求1-4中任一项所要求的用于制备适于注射的水溶液配制剂的方法。
6、按权利要求5所要求用于制备透明水溶液配制剂的方法,其中包括每1摩尔化合物A盐酸盐至少包括1.2摩尔β-环糊精。
7、按权利要求6所要求的方法,其中化合物A盐酸盐对β-环糊精的摩尔比为约1∶1.4。
8、按权利要求5-7中任何一项所要求的方法,其中pH是调节至约为pH=6.0。
9、按权利要求5-8中任何一项所要求的方法,接着将溶液灌注入合适的容器并将其中的溶液灭菌。
10、一种化合物A或其盐酸盐和未取代的或取代的α-,β或γ-环糊精的复合物。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8729823 | 1987-12-22 | ||
GB878729823A GB8729823D0 (en) | 1987-12-22 | 1987-12-22 | Complexes |
GB888804422A GB8804422D0 (en) | 1988-02-25 | 1988-02-25 | Complexes |
GB8804422 | 1988-02-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1034132A true CN1034132A (zh) | 1989-07-26 |
Family
ID=26293226
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN88108916A Pending CN1034132A (zh) | 1987-12-22 | 1988-12-21 | 含哌啶基环戊基庚烯酸衍生物的水溶液配方 |
Country Status (29)
Country | Link |
---|---|
JP (1) | JPH02210A (zh) |
KR (1) | KR890009402A (zh) |
CN (1) | CN1034132A (zh) |
AT (1) | AT395943B (zh) |
AU (1) | AU615245B2 (zh) |
BE (1) | BE1001704A3 (zh) |
CA (1) | CA1328078C (zh) |
CH (1) | CH676665A5 (zh) |
DE (1) | DE3843059A1 (zh) |
DK (1) | DK712888A (zh) |
ES (1) | ES2011727A6 (zh) |
FI (1) | FI885920A (zh) |
FR (1) | FR2624731B1 (zh) |
GB (1) | GB2211737B (zh) |
GR (1) | GR880100854A (zh) |
HU (1) | HU204700B (zh) |
IE (1) | IE61995B1 (zh) |
IL (1) | IL88764A0 (zh) |
IT (1) | IT1224835B (zh) |
LU (1) | LU87411A1 (zh) |
MY (1) | MY103952A (zh) |
NL (1) | NL8803126A (zh) |
NO (1) | NO885689L (zh) |
NZ (1) | NZ227446A (zh) |
PH (1) | PH24982A (zh) |
PL (1) | PL276595A1 (zh) |
PT (1) | PT89301B (zh) |
SE (1) | SE502288C2 (zh) |
ZW (1) | ZW18088A1 (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8814725D0 (en) * | 1988-06-21 | 1988-07-27 | Glaxo Group Ltd | Medicaments |
AU616571B2 (en) * | 1988-10-28 | 1991-10-31 | Shiseido Company Ltd. | Cosmetic composition containing inclusion product with hydroxyalkylated cyclodextrin |
IT1269578B (it) * | 1994-04-22 | 1997-04-08 | Chiesi Farma Spa | Complessi di inclusione multicomponente ad elevata solubilita' costituiti da un farmaco di tipo acido, una ciclodestrina e una base. |
KR100825736B1 (ko) * | 2005-12-07 | 2008-04-29 | 한국전자통신연구원 | 무선 xml 전자 서명 서비스 제공 장치 및 그 방법 |
KR100832740B1 (ko) * | 2007-01-17 | 2008-05-27 | 한국과학기술원 | 분지쇄 아미노산 생성능이 개선된 변이 미생물 및 이를이용한 분지쇄 아미노산의 제조방법 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS503362B1 (zh) * | 1970-06-10 | 1975-02-04 | ||
JPS5443569B2 (zh) * | 1972-07-05 | 1979-12-20 | ||
HU181703B (en) * | 1980-05-09 | 1983-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing aqueus solutuins of water insoluble or hardly soluble vitamines, steroides, localanesthetics, prostanoides and non-steroid and antiphlogistic agents |
JPS57183772A (en) * | 1981-04-29 | 1982-11-12 | Glaxo Group Ltd | Aminocyclopentanol acids and esters, manufacture and medicinal composition |
JPS58116423A (ja) * | 1981-12-28 | 1983-07-11 | Sumitomo Chem Co Ltd | メタノプロスタサイクリン製剤組成物 |
JPS58192821A (ja) * | 1982-04-30 | 1983-11-10 | Dainippon Pharmaceut Co Ltd | 脳神経細胞の酸素欠乏性疾患の治療剤 |
JPS5946228A (ja) * | 1982-09-08 | 1984-03-15 | Zeria Shinyaku Kogyo Kk | 生物学的に活性な有機化合物の水溶性及びリンパ移行性薬剤の製造方法 |
JPS5973576A (ja) * | 1982-09-16 | 1984-04-25 | グラクソ・グル−プ・リミテツド | ピペリジニルシクロペンタノ−ルヘプテン酸塩 |
GB2127406B (en) * | 1982-09-16 | 1986-03-05 | Glaxo Group Ltd | Piperidinlycyclopentanolheptenoic acid salt |
DE3346123A1 (de) * | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | Pharmazeutische praeparate von in wasser schwerloeslichen oder instabilen arzneistoffen und verfahren zu ihrer herstellung |
JPS60150039A (ja) * | 1984-01-17 | 1985-08-07 | Minolta Camera Co Ltd | 水陸両用固定焦点カメラ |
DE3504044A1 (de) * | 1985-02-04 | 1986-08-07 | Schering AG, Berlin und Bergkamen, 1000 Berlin | 9-halogenprostaglandin-clathrate und ihre verwendung als arzneimittel |
JPS6327440A (ja) * | 1986-07-18 | 1988-02-05 | Sanraku Inc | グルコシル化分岐シクロデキストリン含有組成物 |
-
1988
- 1988-12-21 HU HU886537A patent/HU204700B/hu not_active IP Right Cessation
- 1988-12-21 NO NO88885689A patent/NO885689L/no unknown
- 1988-12-21 PT PT89301A patent/PT89301B/pt not_active IP Right Cessation
- 1988-12-21 KR KR1019880017106A patent/KR890009402A/ko not_active Application Discontinuation
- 1988-12-21 PL PL27659588A patent/PL276595A1/xx unknown
- 1988-12-21 IT IT8848702A patent/IT1224835B/it active
- 1988-12-21 DK DK712888A patent/DK712888A/da not_active Application Discontinuation
- 1988-12-21 BE BE8801423A patent/BE1001704A3/fr not_active IP Right Cessation
- 1988-12-21 IE IE382088A patent/IE61995B1/en not_active IP Right Cessation
- 1988-12-21 GB GB8829793A patent/GB2211737B/en not_active Expired - Fee Related
- 1988-12-21 CN CN88108916A patent/CN1034132A/zh active Pending
- 1988-12-21 JP JP63320759A patent/JPH02210A/ja active Pending
- 1988-12-21 AT AT0313088A patent/AT395943B/de not_active IP Right Cessation
- 1988-12-21 ES ES8803876A patent/ES2011727A6/es not_active Expired - Fee Related
- 1988-12-21 FI FI885920A patent/FI885920A/fi not_active Application Discontinuation
- 1988-12-21 AU AU27356/88A patent/AU615245B2/en not_active Ceased
- 1988-12-21 DE DE3843059A patent/DE3843059A1/de not_active Ceased
- 1988-12-21 SE SE8804607A patent/SE502288C2/sv not_active IP Right Cessation
- 1988-12-21 GR GR880100854A patent/GR880100854A/el unknown
- 1988-12-21 NZ NZ227446A patent/NZ227446A/xx unknown
- 1988-12-21 CA CA000586606A patent/CA1328078C/en not_active Expired - Fee Related
- 1988-12-21 CH CH4758/88A patent/CH676665A5/de not_active IP Right Cessation
- 1988-12-21 PH PH37963A patent/PH24982A/en unknown
- 1988-12-21 FR FR8816902A patent/FR2624731B1/fr not_active Expired - Fee Related
- 1988-12-21 LU LU87411A patent/LU87411A1/fr unknown
- 1988-12-21 ZW ZW180/88A patent/ZW18088A1/xx unknown
- 1988-12-21 NL NL8803126A patent/NL8803126A/nl not_active Application Discontinuation
- 1988-12-22 MY MYPI88001508A patent/MY103952A/en unknown
- 1988-12-22 IL IL88764A patent/IL88764A0/xx not_active IP Right Cessation
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